356. Impact of CLSI Breakpoint Changes on Unit-Specific Combination Antibiograms for Gram-Negative Respiratory Isolates

Abstract Background In 2023, the CLSI updated aminoglycoside breakpoints for P. aeruginosa and Enterobacterales. The anticipated decrease in aminoglycoside susceptibility rates resulting from these revised breakpoints will impact empiric antibiotic selection for nosocomial pneumonia. This study aims to evaluate the impact of the new breakpoints on the susceptibility rates of various combination antibiotic regimens for Gram-negative pneumonia at Michigan Medicine. Methods The susceptibility rates of single and combination antibiotic regimens were determined by applying the CLSI breakpoints to 221 non-duplicated, first Gram-negative respiratory isolates obtained from patients in the MICU and SICU of Michigan Medicine in 2021. Combination antibiograms were developed to compare susceptibility rates of various potential empiric regimens based on the 2022 vs. 2023 aminoglycoside breakpoints. Subgroup analyses for P. aeruginosa vs. non-P. aeruginosa were performed. Results Comparisons of unit-specific combination antibiograms against all Gram-negative respiratory isolates using 2022 vs. 2023 breakpoints are shown in Table 1. Based on the 2022 breakpoints, overall susceptibility rates for aminoglycosides were higher than those of anti-pseudomonal β-lactams. The addition of an aminoglycoside improved the susceptibility percentages of a β-lactam up to 23%, allowing similar activity with amikacin-based combination therapy to levofloxacin-based. In contrast, based on 2023 breakpoints, the susceptibility rates of amikacin and gentamicin dropped significantly (85.1 to 58.8% and 81.0 to 56.6%, respectively) and combination with these two agents did not provide additional benefit to the β-lactam backbone. The tobramycin susceptibility rate was minimally affected by the breakpoint changes (82.8% vs. 79.2%). Subgroup analyses demonstrated that the decrease in susceptibility percentages for aminoglycosides was largely driven by the breakpoint changes for P. aeruginosa (Table 1). Conclusion The updated 2023 CLSI breakpoints resulted in a substantial decrease in the susceptibility percentages of amikacin and gentamicin which clinicians need to be aware of when choosing empiric antibiotic treatment. Disclosures Virginia M. Pierce, MD, FIDSA, UpToDate, Inc.: Authorship royalties jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant

susceptibility rates resulting from these revised breakpoints will impact empiric antibiotic selection for nosocomial pneumonia.This study aims to evaluate the impact of the new breakpoints on the susceptibility rates of various combination antibiotic regimens for Gram-negative pneumonia at Michigan Medicine.
Methods.The susceptibility rates of single and combination antibiotic regimens were determined by applying the CLSI breakpoints to 221 non-duplicated, first Gram-negative respiratory isolates obtained from patients in the MICU and SICU of Michigan Medicine in 2021.Combination antibiograms were developed to compare susceptibility rates of various potential empiric regimens based on the 2022 vs. 2023 aminoglycoside breakpoints.Subgroup analyses for P. aeruginosa vs. non-P.aeruginosa were performed.
Results.Comparisons of unit-specific combination antibiograms against all Gram-negative respiratory isolates using 2022 vs. 2023 breakpoints are shown in Table 1.Based on the 2022 breakpoints, overall susceptibility rates for aminoglycosides were higher than those of anti-pseudomonal β-lactams.The addition of an aminoglycoside improved the susceptibility percentages of a β-lactam up to 23%, allowing similar activity with amikacin-based combination therapy to levofloxacin-based.In contrast, based on 2023 breakpoints, the susceptibility rates of amikacin and gentamicin dropped significantly (85.1 to 58.8% and 81.0 to 56.6%, respectively) and combination with these two agents did not provide additional benefit to the β-lactam backbone.The tobramycin susceptibility rate was minimally affected by the breakpoint changes (82.8% vs. 79.2%).Subgroup analyses demonstrated that the decrease in susceptibility percentages for aminoglycosides was largely driven by the breakpoint changes for P. aeruginosa (Table 1).

Conclusion.
The updated 2023 CLSI breakpoints resulted in a substantial decrease in the susceptibility percentages of amikacin and gentamicin which clinicians need to be aware of when choosing empiric antibiotic treatment.
Disclosures Therapy (OPAT) program staff were identified for retrospective review of electronic health records.Weekly labs were highly encouraged in the first month of therapy, and at least monthly thereafter.All patients were reviewed during weekly OPAT rounds.An AE grading tool was derived using Common Terminology Criteria for Adverse Events (CTCAE 2017) to capture common AEs associated with study drugs.Primary study endpoint was occurrence of up to three AEs of any severity during antibiotic therapy.Secondary analyses evaluated risk factors and treatment outcomes associated with AE occurrence using chi-square statistic (MedCalc Software Ltd.).Aerium Therapeutics Inc , Boston, Massachusetts 2 Aerium Therapeutics, Boston, Massachusetts 3 Aerium Therapeutics, Inc., San Jose, California 4 Lausanne University Hospital, Lausanne, Vaud, Switzerland 5 Lavaux Biotech Consulting SARL, Yens, Vaud, Switzerland 6 Aerium Therapeutics Inc., Boston, Massachusetts 1 Pfizer Inc, Cambridge, Massachusetts 2 Pfizer, Cambridge, Massachusetts 3 Pfizer, Inc, Medford, Massachusetts 4 Pfizer, Inc., Pearl River, New York 10 copies/mL.The amino acid (AA) sequence was compared to Wuhan-Hu-1 [7] and M pro substitutions were called if AAFREQ ≥ 10%.Emergent substitutions (ES) were called if observed postbaseline only and called treatment emergent substitutions (TES) if the ES was ≥ 2.5-fold more frequent, had ≥3 additional occurrences, in nirm/r than placebo (PBO).Viral RNA load rebound (VLR) was defined as VL increase at D10 or D14 by ≥ 0.5 log 10 copies/mL from D5 and resulting in a VL ≥ 3.0 log 10 copies/mL.pro ES did not differ between treatment arms.Among those with sequence data available (n=898 nirm/r, n=938 PBO), nirm/r M pro TES were observed in: T98I/del(n=3), E166V (n=3), and W207L/del (n=3) and within the M pro cleavage sites: A5328S/V(n=5) and S6799A/ P/Y (n=4).None of the TES were associated with progression to severe COVID-19.VLR was observed in (6.1% nirm/r, 4.4% PBO) with M pro TES observed in few VLR patients (3.4% in nirm/r and 0% in PBO).Among the M pro TES identified, E166V is an in vitro resistance mutation [8,9].Figure 1 shows the VL trajectories of the 3 patients with E166V, one patient experienced VLR at D10, all effectively controlled the virus by D14 and did not experience severe COVID-19.